Transport of Cisplatin by the Copper Efflux Transporter ATP7B

Safaei, Roohangiz; Otani, Shinji; Larson, Barrett; Rasmussen, Michael L; Howell, Stephen B.

doi:10.1124/mol.107.040980

Cited by 99 publications

(88 citation statements)

References 33 publications

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“…The results obtained with 2008 cells confirmed earlier observations that increased expression of ATP7A (including cells that overexpress ATP7A after transfection) was associated with resistance to various other classes of chemotherapeutic agents (Owatari et al, 2007;Furukawa et al, 2008). Although, like ATP7B (Safaei et al, 2008), ATP7A may transport cDDP directly, it seems unlikely that ATP7A would transport all of the drugs for which resistance has been demonstrated; it is more likely that Sec61␤ controls other types of transporters or alters vesicle pH or that Sec61␤ or ATP7A alters the activity of the vesicle secretory pathway. These hypotheses remain to be tested.…”

Section: Discussionsupporting

confidence: 88%

Sec61β Controls Sensitivity to Platinum-Containing Chemotherapeutic Agents through Modulation of the Copper-Transporting ATPase ATP7A

Abada¹,

Larson

Manorek

et al. 2012

Mol Pharmacol

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The Sec61 protein translocon is a multimeric complex that transports proteins across lipid bilayers. We discovered that the Sec61␤ subunit modulates cellular sensitivity to chemotherapeutic agents, particularly the platinum drugs. To investigate the mechanism, expression of Sec61␤ was constitutively knocked down in 2008 ovarian cancer cells. Sec61␤ knockdown (KD) resulted in 8-, 16.8-, and 9-fold resistance to cisplatin (cDDP), carboplatin, and oxaliplatin, respectively. Sec61␤ KD reduced the cellular accumulation of cDDP to 67% of that in parental cells. Baseline copper levels, copper uptake, and copper cytotoxicity were also reduced. Because copper transporters and chaperones regulate platinum drug accumulation and efflux, their expression in 2008 Sec61␤-KD cells was analyzed; ATP7A was found to be 2-to 3-fold overexpressed, whereas there was no change in ATP7B, ATOX1, CTR1, or CTR2 levels. Cells lacking ATP7A did not exhibit increased cDDP resistance upon knockdown of Sec61␤. Sec61␤-KD cells also exhibited altered ATP7A cellular distribution. We conclude that Sec61␤ modulates the cytotoxicity of many chemotherapeutic agents, with the largest effect being on the platinum drugs. This modulation occurs through effects of Sec61␤ on the expression and distribution of ATP7A, which was shown previously to control platinum drug sequestration and cytotoxicity.

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Section: Discussionsupporting

confidence: 88%

Sec61β Controls Sensitivity to Platinum-Containing Chemotherapeutic Agents through Modulation of the Copper-Transporting ATPase ATP7A

Abada¹,

Larson

Manorek

et al. 2012

Mol Pharmacol

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“…There is now quite a large body of evidence, derived from multiple cell models, that CTR1 regulates the cytotoxicity of DDP by affecting drug uptake (Lin et al, 2002;Holzer et al, 2004aHolzer et al, ,b, 2006aHolzer and Howell, 2006;Larson et al, 2009;Jandial et al, 2009;Safaei et al, 2009) and that the copper exporters ATP7A (Samimi et al, , 2004aSamimi and Howell, 2006) and ATP7B (Katano et al, 2002(Katano et al, , 2003Safaei et al, 2004Safaei et al, , 2008Safaei, 2006) contribute to DDP resistance by enhancing efflux. The absence of CTR1 expression renders yeast and mammalian cells resistant to copper, DDP, carboplatin, and oxaliplatin (Lin et al, 2002;Holzer et al, 2004bHolzer et al, , 2006aLarson et al, 2009), whereas overexpression of CTR1 was found to sensitize cells to the toxic effects of these agents Noordhuis et al, 2008).…”

Section: Ctr1 Controls Uptake Of the Platinum-containing Drugsmentioning

confidence: 99%

Copper Transporters and the Cellular Pharmacology of the Platinum-Containing Cancer Drugs

Howell¹,

Safaei²,

Larson³

et al. 2010

Mol Pharmacol

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243

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Multiple lines of evidence indicate that the platinum-containing cancer drugs enter cells, are distributed to various subcellular compartments, and are exported from cells via transporters that evolved to manage copper homeostasis. The cytotoxicity of the platinum drugs is directly related to how much drug enters the cell, and almost all cells that have acquired resistance to the platinum drugs exhibit reduced drug accumulation. The major copper influx transporter, copper transporter 1 (CTR1), has now been shown to control the tumor cell accumulation and cytotoxic effect of cisplatin, carboplatin, and oxaliplatin. There is a good correlation between change in CTR1 expression and acquired cisplatin resistance among ovarian cancer cell lines, and genetic knockout of CTR1 renders cells resistant to cisplatin in vivo. The expression of CTR1 is regulated at the transcriptional level by copper via Sp1 and at the post-translational level by the proteosome. Copper and cisplatin both trigger the down-regulation of CTR1 via a process that involves ubiquitination and proteosomal degradation and requires the copper chaperone antioxidant protein 1 (ATOX1). The cisplatin-induced degradation of CTR1 can be blocked with the proteosome inhibitor bortezomib, and this increases the cellular uptake and the cytotoxicity of cisplatin in a synergistic manner. Copper and platinum(II) have similar sulfur binding characteristics, and the presence of stacked rings of methionines and cysteines in the CTR1 trimer suggest a mechanism by which CTR1 selectively transports copper and the platinum-containing drugs via sequential transchelation reactions similar to the manner in which copper is passed from ATOX1 to the copper efflux transporters.

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“…We also lack quantitative measurements of copper transport. The indications are that the transport rates are low (12,13). It is assumed that when copper transport across membranes is assayed, it is the permeation step that is rate-limiting.…”

Section: Special Characteristics Of Copper Transportmentioning

confidence: 99%

Copper Transport in Mammalian Cells: Special Care for a Metal with Special Needs

Kaplan

Lutsenko

2009

Journal of Biological Chemistry

143

115

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Copper plays an essential role in human physiology. It is required for respiration, radical defense, neuronal myelination, angiogenesis, and many other processes. Copper has distinct physicochemical properties that pose uncommon challenges for its transport across biological membranes. Only small amounts of copper are present in biological fluids, and essentially none of it exists in a free ion form. These properties and the low redox potential of copper dictate special structural and mechanistic features in copper transporters. This minireview discusses molecular mechanisms through which copper enters and exits human cells. Dietary Acquisition and Excretion of CopperDietary copper is acquired via the small intestine through a process that is not fully understood. Earlier studies showing the major involvement of the mammalian transporter CTR1 in cellular copper uptake (1) led to the assumption that in enterocytes CTR1 mediates the acquisition of dietary copper at the apical membrane. Recent studies questioned this assumption. Cell-surface labeling revealed that the majority (and perhaps all) of surface hCTR1 3 in Caco-2 cells, a model for enterocytes, is located at the basolateral border, i.e. the blood side, and thus cannot mediate apical copper entry (2). Basolateral CTR1 is also observed in renal cells and hepatocytes. Furthermore, in mice with an intestine-specific deletion of CTR1, enterocyte copper levels are higher (and not lower) than in normal mice, arguing against the direct role of CTR1 in apical uptake (3). It seems most likely that in enterocytes some other transporter plays a major role in copper uptake from the fluid that exits the stomach (Fig. 1). The existence of such pathways is supported by the observation that fibroblasts from CTR1 knock-out mice retain ϳ25-30% of their copper uptake (4). Divalent metal transporter DMT1 was suggested as a candidate for copper uptake (5). Other systems not thought of as major copper transporters may accept copper as a surrogate substrate and contribute to the overall copper absorption. Endocytic mechanisms may also contribute to apical copper entry. It is not yet clear how the copper pool from apical dietary uptake in enterocytes interacts with the copper that enters from the blood (Fig. 1).In intestinal cells and tissue, CTR1 was detected at the plasma membrane and in vesicles (2, 6). Thus, CTR1 in enterocytes may take up copper from the blood (as in other cell types) and also from the vesicles in which dietary copper has been sequestered (Fig. 1). This latter role is suggested by the finding that, although the intestinal deletion of CTR1 results in high copper levels in enterocytes, this copper is not available (3). It is tempting to speculate that CTR1 is uniquely positioned to make copper bioavailable either because it has a specific recognition mechanism and/or it is directly coupled to the copper chaperones that distribute copper for further utilization.After copper crosses the membrane, it is delivered to acceptor proteins by cytosolic metallochaperone...

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Transport of Cisplatin by the Copper Efflux Transporter ATP7B

Cited by 99 publications

References 33 publications

Sec61β Controls Sensitivity to Platinum-Containing Chemotherapeutic Agents through Modulation of the Copper-Transporting ATPase ATP7A

Sec61β Controls Sensitivity to Platinum-Containing Chemotherapeutic Agents through Modulation of the Copper-Transporting ATPase ATP7A

Copper Transporters and the Cellular Pharmacology of the Platinum-Containing Cancer Drugs

Copper Transport in Mammalian Cells: Special Care for a Metal with Special Needs

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